Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Roxithromycin (RU 28965) a new semisynthetic macrolide has been reported to display an antibacterial spectrum and activity in vitro similar to those of others macrolides. However, roxithromycin seems more efficient than erythromycin in in vivo experimental infections (mice). We have previously reported that roxithromycin increases the ability of human neutrophils (PMN) for bactericidal activity (S. aureus) or phagocytosis (K. pneumoniae) in vitro without altering other PMN functional parameters. In this study, roxithromycin (single dose-300 mg) was given to 6 human volunteers. The neutrophils collected 90 min after ingestion display a significant increased ability to phagocytose and kill S. aureus and K. pneumoniae. Furthermore chemotaxis, oxidative burst and myeloperoxidase activity of the PMN after roxithromycin ingestion were enhanced compared to those of PMN before ingestion. This discrepancy between immunomodulating effect of roxithromycin in vitro and in vivo outlines the complexity of in vivo experimental models and requires further studies in vivo in particular in patients suffering from sepsis.
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PMID:[Interaction of roxithromycin with human polymorphonuclear neutrophils in vitro and ex vivo]. 284 6

Degradation of structural elements and excessive consumption of humoral factors, especially of plasma proteinase inhibitors, by proteolysis and/or oxidation is a major cause of multiple organ failure in sepsis or septic shock. Such pathobiochemical reactions seem to be induced primarily by extracellularly liberated lysosomal proteins from PMN granulocytes (e.g. elastase, cathepsin G, myeloperoxidase, lactoferrin) as well as oxygen radicals produced during extensive phagocytosis. In clinical studies on septicemia and septic shock the consumption of plasma proteins including proteinase inhibitors was inversely correlated to the liberation of lysosomal factors, especially the granulocytic elastase. Administration of relatively specific elastase-cathepsin G-inhibitors (Bowman-Birk inhibitor, eglin) in experimental septicemia proved to be a promising therapeutic approach to reduce consumption of plasma proteinase inhibitors and development of interstitial lung edema in severe inflammation.
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PMID:Pathobiochemistry of sepsis: role of proteinases, proteinase inhibitors and oxidizing agents. 352 75

Burns wound sepsis is not only the most common but also the most severe complication following extensive thermal injury. One conceivable explanation of this problem is a reduced capacity of the polymorphonuclear neutrophil leucocytes of these patients to combat the invading microbes. Fifty patients (42 male and 8 female) with deep dermal burns, covering 20-90 per cent of the total body surface area, were investigated from immediately after the injury until death or until healing of the wounds. The following functions of the neutrophil granulocytes were studied: chemotaxis and random migration utilizing a modified Boyden chamber technique, phagocytosis of Staph. aureus and IgG-coated latex particles, bactericidal capacity, e.g. killing of Staph. aureus and the neutrophil granulocyte content of: myeloperoxidase, lactoferrin, and chymotrypsin-like cationic protein. The presence of stimulators and inhibitors of the granulocyte functions was studied using gel filtration of the patient's serum on Sephacryl gel columns. Sera from all patients obtained within the first 1-3 days post-burn contained significantly increased amounts of heat-labile chemokinetic stimulating activity. Sera obtained between days 4 and 10 after injury contained significantly decreased amounts of heat-stable chemokinetic stimulating activity. Reduced chemokinetic activity was found during the third and fourth weeks following major burns (greater than or equal to 40 per cent) due to the presence of one or both heat-stable chemokinetic inhibitory activities. During the second week post-burn patients with burns larger than 40 per cent of the body surface area who showed an inhibition of chemotaxis, also had defects in phagocytosis, and often impaired bactericidal capacity concomitant with lower contents than normal of the granular enzymes. A hyaluronic acid preparation in low concentrations was found to counteract the migration inhibitory effect demonstrated in vitro in sera from patients with severe burns. Based upon these results a series of patients with severe burns and impaired functions of the neutrophil granulocytes have been treated with small amounts of this hyaluronic acid preparation subcutaneously. Very promising results have been noticed, similar to those found in vitro.
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PMID:Neutrophil granulocyte functions in severely burned patients. 402 46

A 52 yr old Caucasian female (F. E.) had hemolytic anemia, a leukemoid reaction, and fatal sepsis due to Escherichia coli. Her leukocytes ingested bacteria normally but did not kill catalase positive Staphylococcus aureus, Escherichia coli, and Serratia marcescens. An H(2)O(2)-producing bacterium, Streptococcus faecalis, was killed normally. Granule myeloperoxidase, acid and alkaline phosphatase, and beta glucuronidase activities were normal, and these enzymes shifted normally to the phagocyte vacuole (light and electron microscopy). Intravacuolar reduction of nitroblue tetrazolium did not occur. Moreover, only minimal quantities of H(2)O(2) were generated, and the hexose monophosphate shunt (HMPS) was not stimulated during phagocytosis. These observations suggested the diagnosis of chronic granulomatous disease. However, in contrast to control and chronic granulomatous disease leukocytes, glucose-6-phosphate dehydrogenase activity was completely absent in F. E. leukocytes whereas NADH oxidase and NADPH oxidase activities were both normal. Unlike chronic granulomatous disease, methylene blue did not stimulate the hexose monophosphate shunt in F. E. cells. Thus, F. E. and chronic granulomatous disease leukocytes appear to share certain metabolic and bactericidal defects, but the metabolic basis of the abnormality differs. Chronic granulomatous disease cells lack oxidase activity which produces H(2)O(2); F. E. cells had normal levels of oxidase activity but failed to produce NADPH due to complete glucose-6-phosphate dehydrogenase deficiency. These data indicate that a complete absence of leukocyte glucose-6-phosphate dehydrogenase with defective hexose monophosphate shunt activity is associated with low H(2)O(2) production and inadequate bactericidal activity, and further suggest an important role for NADPH in the production of H(2)O(2) in human granulocytes.
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PMID:Complete deficiency of leukocyte glucose-6-phosphate dehydrogenase with defective bactericidal activity. 440 Dec 71

This review has concentrated on clinical syndromes for which a congenital basis of polymorphonuclear neutrophil dysfunction has been identified. The first clinical syndrome found to be associated with dysfunctional polymorphs was chronic granulomatous disease of childhood. Identification of a cellular defect in oxidative metabolism and microbicidal activity of polymorphonuclear neutrophils from patients with CGD stimulated intense investigation of the function of phagocytes in several clinical entities characterized by increased susceptibility to infection. Other diseases with a probable congenital basis for polymorph dysfunction include Chediak-Higashi syndrome, myeloperoxidase deficiency, severe glucose-6-phosphate dehydrogenase deficiency, and Down's syndrome. Functional defects have also been identified in neutrophils with morphologic abnormalities, such as the Pelger-Huet anomaly and the May-Hegglin anomaly, and in neutrophils without alkaline phosphatase or with a disorder of the glutathione system. The evidence for a relation between these cellular disorders and susceptibility to infection is tentative. Patients with congenital disorders of polymorphonuclear neutrophil microbicidal function frequently suffer prolonged infections in spite of appropriate antimicrobial therapy, and severe lesions recur with discouraging frequency. These lesions are usually soft tissue or bone abscesses, and the etiologic agents are typically staphylococci, gram-negative enteric species, or fungi. The infectious disease problems of patients with phagocytic cell disorders are usually quite distinct from the problems of patients without immunoglobulins or with complement deficiency. Patients with agammaglobulinemia, for example, suffer recurrent septicemia or meningitis due to Streptococcus pneumonia or H. influenzae. Septicemia, especially with the pyogenic bacterial species, is unusual in patients with polymorphoinuclear dysfunction. A major contribution of the currently intense investigation of cells from patients with congenital disorders of phagocyte function has been the greatly increased understanding of the molecular events necessary for the normal function of these cells. The role of the oxidative metabolic burst during phagocytosis has been clearly identified as essential to the microbicidal function of polymorphs and monocytes, and the glutathione system has been identified as essential to the regulation of these oxidative reactions. It is anticipated that these studies may lead to practical methods for "stimulating the phagocytes" in patients with increased susceptibility to infection.
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PMID:Congenital disorders of the function of polymorphonuclear neutrophils. 625 30

Ethanol is a potent immunosuppressive agent that impairs neutrophil effector function. The purpose of this study was to determine whether granulocyte colony-stimulating factor (G-CSF), a cytokine that increases neutrophil number and functional activity, could prevent the ethanol-induced impairment of antibacterial host defense. Rats were injected with human recombinant G-CSF for 2 days. Eight hr after the last injection of G-CSF, animals were infused with ethanol (or saline) for 1 hr before the subcutaneous injection of live Escherichia coli. The infusion of alcohol was continued after the bacterial challenge and produced blood alcohol levels of 275-300 mg/dl. In control animals, the injection of E. coli resulted in a marked leukopenia. There was an influx of leukocytes into the subcutaneous space where the bacteria were injected, and neutrophil accumulation in tissues adjacent to the focus of infection (i.e., dorsal skin and muscle). Based on myeloperoxidase activity, there was no detectable accumulation of neutrophils in other soft tissues. In acutely intoxicated rats, leukocyte migration to the inflammatory site was impaired, and the number of viable bacteria isolated from the subcutaneous pocket was markedly increased. G-CSF prevented the sepsis-induced leukopenia, increased the influx of neutrophils in to the infection site, reduced the number of bacteria in the subcutaneous lavage fluid, and decreased the incidence of bacteremia in ethanol-treated rats when compared with rats not receiving G-CSF. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil recruitment selectively to the site of infection and that can be used to ameliorate the ethanol-induced impairment in bacterial host defense.
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PMID:Granulocyte colony-stimulating factor prevents ethanol-induced impairment in host defense in septic rats. 750 76

Many studies indicate a pivotal role for neutrophil adhesion in sepsis-associated lung injury. Neutrophil adhesion to endothelium depends on activation and expression of selectin and integrin adhesion receptors. We studied the effects of pretreatment with a dual-binding porcine anti-E- and anti-L-selectin monoclonal antibody (EL-246) on a porcine model of sepsis-induced lung injury. Four groups were studied for 5 h. Group 1 (control animals) received intravenous saline only. Group 2 (septic) received a 1-h infusion of Pseudomonas aeruginosa. Group 3 (EL-246 pretreatment) received EL-246 (1 mg/kg) prior to Pseudomonas infusion. Group 4 (EL-246 controls) received EL-246 infusion only. Group 2 animals showed rapid, significant decline in arterial pH and oxygen tension whereas, in Group 3, physiologic deterioration was significantly attenuated. Bronchoalveolar lavage at 5 h showed a significant increase in neutrophil count and protein content in Group 2. Group 3, however, showed no significant differences in these parameters compared with control animals. Despite severe neutropenia, lung myeloperoxidase content at 5 h was significantly reduced in Group 3 compared with Group 2. There was no significant difference in pulmonary and systemic hemodynamics between Groups 2 and 3. Group 4 animals exhibited a transient neutropenia, but otherwise no other differences in measured parameters were found compared with Group 1 control animals. In conclusion, EL-246 significantly reduced neutrophil accumulation in lung and attenuated sepsis-induced lung injury, but failed to attenuate deranged pulmonary and systemic hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A dual-binding antibody to E- and L-selectin attenuates sepsis-induced lung injury. 754 Dec 77

It has been proposed that the reduction in mortality in animal models of sepsis by activated protein C (APC) is mediated by an antiinflammatory property rather than the well-characterized anticoagulant action. Human recombinant APC was examined for potential antiinflammatory activity in the pentobarbital-anesthetized rat. In the dermal reversed passive Arthus model, APC (20.0 mg/kg/h, i.v.) elevated clotting time 10-fold 3 h after the Arthus challenge, at which time, the wet-weights from Arthus dermal samples in APC rats (120.0 +/- 1.5 mg, n = 10) did not differ from controls (120.1 +/- 1.5 mg, n = 10) but were 30% heavier than remote noninflamed skin (92.0 +/- 2.0 mg, n = 10), indicating that APC treatment did not diminish tissue edema associated with immune-complex deposition. Skin-lesion myeloperoxidase (neutrophil marker enzyme) activities from APC rats were not significantly different from controls but was 21-fold more than remote noninflamed skin, indicating that APC treatment did not diminish dermal recruitment of neutrophils. In the intestinal ischemia/reperfusion model, 1 h complete occlusion of the superior mesenteric artery and an additional 4 h reperfusion was associated with a 2.87-fold increase in lung myeloperoxidase activity compared to sham-operated rats. APC (1.0 mg/kg/h, i.v.) did not diminish the elevation in this index of lung neutrophil sequestration. In conclusion, APC did not produce an antiinflammatory effect in the rat models used.
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PMID:Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation. 771 66

The proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) are produced within the lung during sepsis, and may induce neutrophil sequestration resulting in neutrophil-mediated lung injury. We hypothesized that, if there is a cause and effect between TNF alpha or IL-1 production and lung neutrophil sequestration during chronic sepsis, TNF alpha mRNA and IL-1 mRNA levels in the lung after cecal ligation and puncture should correlate with the number of sequestered neutrophils as measured by the myeloperoxidase (MPO) content of the lung. To test this hypothesis, Swiss Webster mice were subjected to varying degrees of infectious challenge by single and double-puncture cecal ligation and puncture, or simultaneous antibiotic treatment, and their lungs and blood were harvested at 24 h. Lung TNF alpha and IL-1 beta mRNAs were measured by the reverse-transcription differential polymerase chain reaction, and MPO was measured by colorimetric assay. TNF alpha serum levels showed no correlation with the MPO content of the lung, whereas IL-1 levels were undetectable. Lung TNF alpha mRNA correlated weakly, and IL-1 beta mRNA exhibited a strong correlation with lung MPO (r = .9, p < .01), but administration of anti-TNF alpha- or anti-IL-1-neutralizing antibodies did not prevent a rise in lung MPO. IL-1 beta mRNA in bronchoalveolar macrophages correlated well with whole lung tissue IL-1 beta mRNA levels (r = .91, p < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Passive immunization against tumor necrosis factor and interleukin-1 fails to reduce lung neutrophil sequestration in chronic sepsis. 774 65

Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF-alpha) synthesis or block its interactions with cellular receptors. Mice were treated intraperitoneally with cationic liposomes containing 200 micrograms of either a pCMV (cytomegalovirus)/p55 expression plasmid that contains the extracellular domain and transmembrane region of the human p55 TNF receptor, or a pcD-SR-alpha/hIL-10 expression plasmid containing the DNA for human interleukin 10. 48 h later, mice were challenged with lipopolysaccharide (LPS) and D-galactosamine. Pretreatment of mice with p55 or IL-10 cDNA-liposome complexes improved survival (p < 0.01) to LPS-D-galactosamine. In additional studies, intratracheal administration of IL-10 DNA-liposome complexes 48 h before an intratracheal LPS challenge reduced pulmonary TNF-alpha levels by 62% and decreased neutrophil infiltration in the lung by 55% as measured by myeloperoxidase activity (both p < 0.05). Gene transfer with cytokine inhibitors is a promising option for the treatment of both the systemic and local sequelae of septic shock.
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PMID:Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. 776 15


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